Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention by treatment with a neuroactive flavonoid, morin

Abstract

Psychosocial stress and biological predispositions are linked to mood and personality disorders related to psychiatric behaviors. Targeting neuroinflammation and oxidative stress has been recognized as a potential strategy for the prevention of psychosocial stress-induced psychiatric disorders. Morin, a bioactive compound isolated from mulberry leaf has been shown to produce antiamnesic, antipsychotic and anti-inflammatory effects relative to ginseng, a well-known adaptogen. Hence, the present study investigated the effect of morin on social-defeat stress (SDS)-induced behavioral, neurochemical, neuroimmune and neurooxidative changes in mice using intruder-resident paradigm. The intruder male mice were distributed into 6 groups (n = 10). Groups 1 (normal-control) and 2 (SDS-control) received normal saline, groups 3–5 had morin (25–100 mg/kg) while group 6 received ginseng (50 mg/kg) intraperitoneally daily for 14 days. Thirty minutes after treatment from days 7–14 onwards, mice in groups 2–6 were exposed to SDS for 10 min physical and psychological confrontations respectively with aggressive-resident mice. Neurobehavioral effects (locomotor activity, cognitive performance, anxiety- and depressive-like behavior) were assessed on day 14. Biomarkers of oxidative/nitrergic stress and neuroinflammation; acetylcholinesterase (AChE) and glutamic-acid decarboxylase-67 (GAD67) were measured in the striatum, prefrontal-cortex and hippocampus. Behavioral deficits induced by SDS were attenuated by morin and ginseng. Both morin and ginseng decreasedmalondialdehyde, nitrite levels and increased glutathione concentrations in the brain regions. They also reduced inflammatory mediators (TNF-α, IL-6, COX-2 and NF-κB), AChE activity and Nox-2 expression in the specific brain regions. However, morin increased the levels of GAD67 in the striatum, prefrontal-cortex and hippocampus in contrast to ginseng. Our results suggest that morin mitigates SDS-induced neurobehavioral deficits through enhancement of GAD67, inhibition of AChE activity, oxidative stress, Nox-2 and neuroinflammatory pathways.